1. Field of the Invention.
The present invention relates to compositions and methods for use in the treatment of pathologies associated with insulin deficiency.
2. Description of Related Art.
In continuous infusion systems, a fluid containing a therapeutic agent is pumped from a reservoir, usually to a subcutaneous, intravenous, or intraperitoneal depot. The reservoir, which is refilled periodically, is attached to the patient's body, or is implanted in the patient's body. In either case, the patient's body heat and body motion, plus turbulence in the tubing and pump impart a relatively high amount of thermo-mechanical energy to the formulation. In the interest of minimizing the frequency with which the reservoir is refilled, and of minimizing the size of the reservoir, stable formulations having a relatively high concentration of the therapeutic agent are highly advantageous. Consequently, stable formulations of therapeutic agents are particularly important for use in delivery devices that expose these agents to elevated temperatures and/or mechanical stress.
A typical context for such continuous infusion systems involves the treatment of diabetes and related syndromes by the administration of insulin and its analogs. Stable insulin formulations, for example, are required for use in continuous infusion systems and related devices. Insulin formulations for implantable pump use preferably possess several characteristics including exceptional physical and chemical stability. Commercial insulin preparations are typically designed to have a stable shelf life of 1 to 2 years when stored at refrigerator temperatures in glass vials or cartridges. In actual use however, insulin is typically used in a syringe (for immediate injection) in an insulin pump (for up to a week) or in an insulin pen (for a week or two). Formulations of insulin for use in continuous infusion systems should remain soluble and substantially free of aggregation, even though subjected to the patient's body heat and motion for periods ranging from a few days to several months. In this context, instability is promoted by the higher insulin concentrations that are desirable for continuous infusion systems and by the thermo-mechanical stress to which formulations are exposed in continuous infusion systems. Therefore, improvement in the physical and chemical stability of concentrated insulin formulations is urgently needed to facilitate their use in continuous infusion systems. In particular, the preferred insulin formulations for implantable pump use possess chemical and physical stability in the harsh environment of the implantable pump. The formulations are typically stable in a glass cartridge or vial during long term storage and in addition should be stable for at least 90 days at physiological temperatures, all while being constantly agitated inside a metal container (typically titanium) having a relatively hydrophobic surface (e.g. TiO2 with an average contact angle of more than 60°).
The development of insulin analogs for the treatment of diabetes allows for the generation of novel formulations for use in continuous infusion devices. For example, rapid-acting insulins, known as monomeric insulin analogs, are well-known in the art, and are disclosed in Chance, et al. U.S. Pat. No. 5,514,646, issued May 7, 1996; Brems, et al., Protein Engineering, 6:527-533 (1992); Brange, et al., EPO publication No. 214,826 (published Mar. 18, 1987); and Brange, et al., Current Opinion in Structural Biology 1:934-940 (1991). Monomeric insulin analogs are absorbed much faster than insulin, and are ideally suited for postprandial control of blood glucose levels in patients in need thereof. They are also especially well-suited for administration by continuous infusion for both prandial and basal control of blood glucose levels because of their rapid absorption from the site of administration. Unfortunately, monomeric insulin analog formulations have a propensity to aggregate and to become unstable when exposed to thermo-mechanical stress. Aggregation may even be manifested as precipitation of higher-order insulin species. In this way, aggregation can prevent reproducible delivery of effective therapeutic doses of monomeric insulin analogs, and may also cause irritation at the administration site or a more systemic immunological response. Consequently, insulin analog formulations stabilized against aggregation are highly desirable.
While a number of aqueous formulations which stabilize insulin compositions have been identified in the art, the destabilization of insulin in solution continues to create problems for medical practitioners. Consequently, there is a need for new insulin compositions which overcome the problems of the prior art. This need is fulfilled by the invention that is described below.